Year: 2006
Type: article
Abstract: Activation of the HPA axis is among the first measurable physiological responses to cerebral ischemia, and clinical and experimental evidence suggests that glucocorticoid exposure prior to and following stroke is a critical determinant of survival and functional outcome following ischemic attacks.Indeed, perinatal environment may be a particularly important determinant of hypothalamic-pituitary-adrenal (HPA)-axis efficiency and may influence the onset of psychopathology and age-related disease.In rodents, altering mother-infant interactions can permanently affect the physiological and behavioral responses of the progeny to stress.The present body of work examined the effects of brief maternal separation (BMS), extended maternal separation (EMS), and prenatal stress (PNS) on stress responsivity and stroke recovery in adult male mice.Despite improved HPA-axis responsivity to acute stressors, BMS male mice that underwent 60 min MCAO in adulthood had significantly more ischemia-induced neuronal death, and increased functional deficits.The increase in corticosterone-induced neuronal death, and increased expression of pro-inflammatory cytokines and edema, suggest that BMS mice are more sensitized as adults to the detrimental effects of elevated corticosterone during ischemia.Female BMS mice exhibited similar exacerbation of stroke outcomes to the males when exposed to the MCAO model of focal ischemia, but not the CA/CPR model of global ischemia.Indeed, UD females had increased anxiety iii like behaviors and increased dendrtitic arborizaton in the basolateral amygdala following CA/CPR compared to BMS females, while BMS females had increased neuronal death and functional deficits resulting from 60 min MCAO.Unlike BMS, the EMS and PNS paradigms had minimal consequences on focal ischemic outcome in male and female mice.EMS and PNS males had significantly greater deficits in left paw use at 72 hr reperfusion than UD males, and that PNS males had significantly lower measures of postischemic edema and corticosterone than UD and EMS males.Perinatal female EMS mice had significantly more neuronal damage than PNS, but not UD, females, while all three groups exhibited similar behavioral deficits following stroke surgery.Though additional experiments are necessary to more clearly establish the responsible mechanisms, these studies clearly demonstrate that neonatal environment can drastically affect adult sensitivity to ischemic injury and changes to dendritic morphology by altering the HPA axis and inflammatory responses.Psychobiological determinants of stroke outcome are not limited, however, to manipulations of the early environment.Indeed, affiliative social interaction via pair housing was determined to decrease infarct size, functional deficits, and intra-ischemic measures of inflammation in comparison to socially isolated mice.In addition, pair housing reversed the negative consequences of BMS, with pair housed BMS males exhibiting decreased infarct and functional deficits compared to socially isoloated BMS males.In contrast to affiliative social behaviors, post-stroke depression (PSD) can impair functional recovery and increase mortality following stroke.Similar to ischemia, depression involves glucocorticoid and inflammatory mechanisms, yet the physiological mechanisms of underlying PSD are unknown.The final experiments investigated the roles of glucocorticoids and interleukin-1 in post-stroke anhedonia.The data suggest that anhedonia is a valid index of post-stroke depressive-like behavior in mice.Indeed, MCAO significantly decreased sucrose consumption in comparison to SHAM surgery mice.Furthermore, IL-1ra effectively attenuated the decreased sucrose consumption observed following stroke, while treatment with metyrapone or mifepristone had no effect on reversing the anhedonia.Together, the experiments described in this dissertation suggest that psychobiological processes that alter glucocorticoid exposure significantly influence neuronal survival and functional outcome following cerebral ischemia in adult mice.Indeed, perinatal determinants of HPA axis development, social modulation of stress responsivity, and post-stroke depression are important mediators of peri-ischemic glucocorticoid-and inflammatory cytokine exposure, significantly influencing physiological and behavioral outcomes.v
Author: Tara K.S. Craft
Institution: The Ohio State University
Language: English
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2521400569